Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel γ-secretase modulator, E2212, in healthy human subjects.

E2212, a novel γ-secretase modulator, is under development for the treatment of Alzheimer's disease. The safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses (10-250 mg, double-blind, placebo-controlled, randomized) of E2212 were evaluated. In this phase I clinical trial, E2212 was found to be well tolerated in single doses. Maximum tolerated dose was not achieved up to 250 mg. Most AEs were mild to moderate in severity with no identifiable dose related pattern. There were no clinically significant findings on physical and ophthalmologic examinations as well as vital signs, laboratory, ECG and C-SSRS assessments. E2212 was rapidly absorbed, with median tmax values ranging from 0.5 to 1.0 h. E2212 exhibited biphasic disposition with the terminal t1/2 of 12.5-19.0 h. Renal excretion was the minor pathway for E2212 elimination. Increased PD response (reduction in plasma concentrations of Aß(x-42)) was observed with increasing doses. The maximum PD response was observed in the highest dose 250 mg cohort, with ΔAUAC(0-24 h) of 44.1% and Amax of 53.6%. These results support further clinical development of E2212.

Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population.

Bronchial asthma is a common inflammatory disease caused by the interaction of genetic and environmental factors. Through a genome-wide association study and a replication study consisting of a total of 7,171 individuals with adult asthma (cases) and 27,912 controls in the Japanese population, we identified five loci associated with susceptibility to adult asthma. In addition to the major histocompatibility complex and TSLP-WDR36 loci previously reported, we identified three additional loci: a USP38-GAB1 locus on chromosome 4q31 (combined P = 1.87 × 10(-12)), a locus on chromosome 10p14 (P = 1.79 × 10(-15)) and a gene-rich region on chromosome 12q13 (P = 2.33 × 10(-13)). We observed the most significant association with adult asthma at rs404860 in the major histocompatiblity complex region (P = 4.07 × 10(-23)), which is close to rs2070600, a SNP previously reported for association with FEV(1)/FVC in genome-wide association studies for lung function. Our findings offer a better understanding of the genetic contribution to asthma susceptibility.

Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma.

Thymic stromal lymphopoietin (TSLP) triggers dendritic cell--mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP)-1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter--reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patients with childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively). We further examined the effects of corticosteroids and a long-acting ß(2)-agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I:C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P = 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14-1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I:C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.

[Influence of changing inhalation device from separate diskus of salmeterol and fluticasone propionate to combination diskus in asthma patients].

PURPOSE: Salmeterol xinafoate (salmeterol) and fluticasone propionate (FP) combination (SFC) was reported to enhance improvement of lung function compared with concurrent administration of the two drugs from separate devices. However, there was no report of asthma control improvement comparing SFC and concurrent administration with separate inhalers in real-life general practice in Japan We evaluated asthma control improvement and patients' perception of SFC in asthmatic patients changing from concurrent therapy with salmeterol and FP with separate devices, Diskus. METHOD: Treatment were changed to SFC in one hundred and three patients with mild to severe asthma receiving concurrent administration of salmeterol and FP with separate Diskus. Asthma control test (ACT), easy asthma program (EAP) and peak expiratory flow (PEF) were performed before and after 2 or 4 weeks of SFC treatment. RESULTS: SFC treatment increased ACT score by 1.6 point and improved asthma control status measured by EAP. Forty percent of the patients felt their asthmatic symptoms improved, of which 60% recognized their improvement started within a few days. The use of short-acting inhaled beta2-agonist was decreased in 67% of the patients, and exercise-induced dyspnea was improved in 30% of the patients. In addition, SFC was considered as convenient by 96% of the patients and made a good impression on 86% of the patients. CONCLUSION: This study demonstrates that SFC improves asthma control and better satisfaction than concurrent therapy with separate devices in asthmatic patients in real-life general practice.

Cost-effectiveness of including salmeterol in asthma therapy in a primary care setting in Japan.

To discuss and estimate the clinical and economic benefits obtained during combination therapy with inhaled corticosteroids (ICS) plus salmeterol (SLM) for Japanese patients with asthma on the basis of the Global Initiative for Asthma (GINA) Guidelines. Fifty-four cases aged>16 years with either moderate persistent asthma (step 3) or severe persistent asthma (step 4) were assessed in a retrospective survey. Participants must have been a patient at the author's clinic continuously from June 2001 and been users of SLM for more than one year. Signed informed consent was obtained. Both clinical and economic components of SLM use in asthma therapy over the past two years were evaluated. Cost analyses revealed that SLM use significantly reduced medical costs of leukotriene receptor antagonist and short-acting inhaled beta(2)-agonists. Moreover, clinical outcomes (e.g. symptom-free day) were significantly improved after initiation of SLM. Sensitivity analyses confirmed that use of SLM is cost-effective. Combination therapy with inhaled corticosteroids and SLM on the basis of GINA guidelines appears to be efficacious and cost effective for the treatment of moderate or severe persistent asthma in Japanese patients.